1. Pharmacology of Glaucoma
TARIQ ALASBALI

2. Glaucoma: Treatment Goal
“The goal of glaucoma treatment is to preserve the visual field of patients and prevent the loss of visual function associated with the disease.”
Ref: Survey of Ophthalmology; 2003 Vol. 48(1): S1-S3

3. What is a target IOP?
“The IOP at which the rate of retinal ganglion cell loss is no greater than the age related loss.”Brubaker

4. AAO Guidelines: Target IOP
% reduction from baseline
Ref: Survey of Ophthalmology 2003; 48 (suppl 1); 53-57

5. Target IOP is based on over-all glaucomatous damage
Optic Nerve Damage
Risk Factors VF
IOP

6. REQUIREMENT OF AN AGENT FOR PROVEN 24-HOUR CONTROL
FLUCTUATIONS IN IOP
REQUIREMENT OF AN AGENT
FOR PROVEN 24-HOUR CONTROL
Not only controlling peak IOP is important but the drug should also control fluctuations in IOP

7. In POAG what is your first line drug and why?
What are your next choices?

8. Ineffective Or Side effect Effective Not at Target
PG/PA
Target Achieved:
Continue to Follow
Target Not Achieved
Ineffective Or Side effect
Effective
Not at Target
Continue & Return to Top
with Additional Drug
Discontinue & Return to Top
with Different Drug
Beta-Blockera
Brimonidinea
Topical CAIa
Cholinergicb
Oral CAIb
a: Order depends on side effects & contraindications
b: Secondary Drugs Consider other therapies also

9. Primary Drug Classes Prostaglandin Analogues / Prostamides
Beta Adrenergic Antagonists
‘Beta blockers’
Alpha 2 Adrenergic Agonists
Carbonic Anhydrase Inhibitors

10. Primary Drug Classes
A meta-analysis of 27 articles suggests that bimatoprost, travoprost, latanoprost, and timolol are the most effective intraocular pressure-reducing agents in POAG and OH patients.
Ophthalmology Jul;112(7):

11. Prostaglandin Analogues is approved by (FDA), as a first line treatment for elevated (IOP) associated with open angle glaucoma or ocular hypertension
medscape.com assessed on 18/11/03

12. Secondary Drug Classes
Parasympathomimetics
Cholinergic (Muscarinic) Agonists
Acetylcholinesterase inhibitors
Non-selective Adrenergic Agonists
Rarely used

13. % ↓IOP
Mean ↓IOP
Medication
Drug class
~ 30%
6-8 mm Hg
7-8 mm Hg
Latanoprost
Bimatoprost
Travoprost
PGA
~25%
~6mm Hg
Timolol
B-blocker, non selective
20-25%
2-6 mm Hg
Brimonidine
A-2 adrenergic
~20%
4-5 mm Hg
Betaxolol
B-blocker, selective
15-20%
3-5 mm Hg
Dorzolamide
CAI

14. Prostaglandin Analogues & Prostamides: Dosing & Preparations
Latanoprost
Travoprost
Bimatoprost
All QHS

15. Latanoprost: Instillation at 9 pm27 25 23 21 19 17 15 18 24 03 06 09 12
Time (hours) I O P ( m H g )
Peak IOP
Latanoprost when instilled at 9 pm effective controlled IOP at 9 am
Baseline
Latanoprost

16. Prostaglandin Analogues & Prostamides: Mechanism of Action
Increase uveoscleral outflow
At least 8 PG receptor subtypes
Latanoprost and Travoprost
analogues of PGF2α bind known PG receptors
Whether Bimatoprost works in the same way seems to depend on whether you work for Allergan or Pfizer

17. Prostaglandin Analogues & Prostamides: Mechanism of Action
Free acid is active component at PG receptors
Requires enzymatic cleavage
Latanoprost and Travoprost are esters
Esterases present in cornea and a.c.
Bimatoprost is an amide.

18. Prostaglandin Analogues & Prostamides: IOP Response
Expected IOP lowering:
~30%
Latan = Trav=Bim (1)
Another finding difference, generally < 1mmHg (2)
Recent Meta-Analysis (3)
Latan: 31% peak, 28% trough
Trav: 31 % peak, 29% trough
Bim: 33 % peak, 28% trough
Onset of IOP lowering
2-4 hours
Peak Effect
8-12 hours
Wash Out
4-6 weeks
1-Clin Experiment Ophthalmol. 2006:34(8):
2-Adv Ther Jul-Aug;21(4):
3-Ophthalmology.2005:112(7):

19. PROSTAGLANDIN: Proven for 24 hour IOP Control
Latanoprost, travoprost, and bimatoprost
were effective in reducing the 24-h IOP
in patients with XFS and OH
Eye (2007) 21, 453–458
Ref: Invest Ophthalmol Vis Sci 2000; 41:

20. Prostaglandin Analogues & Prostamides: Interactions with Other IOP drugs
Theoretically expected to have poor additivity with parasympathomimetics
Clinically, this has not been proven
Good additivity to others

21. Prostaglandin Analogues & Prostamides: Side Effects
Lash Changes
Pigmentation
Iris
Periocular skin
Pro-Inflammatory
Hyperemia of Conjunctiva
Uveitis
CME
Reactiviation of HSV keratitis

22. Beta-Blocker Preparations
Non-selective
Timolol 0.25%, 0.5%
Gel-vehicle (Timoptic XE 0.25%, 0.5%)
Levobunolol 0.25%, 0.5%
Befunolol
Metipranolol
Beta 1 Selective
Betaxolol 0.25%, 0.5%

23. Beta-Blocker Preparations
With ISA
Cartelol 0.5% - 2%
Pindolol 2%

24. Beta Blockers: Mechanism of Action
Mediated through beta 2 adrenergic receptors
Decreases aqueous production

25. Beta Blockers: Dosing BID dosing except gel-vehicle
Increasing beyond BID of no help
Timoptic XE once daily in a.m.

26. Beta Blockers: IOP Response
Expected IOP lowering:
~25%
Peak effect
Two hours
Wash out
2-5 weeks

27. Use w/ systemic β-blocker:
Beta Blockers
Use w/ systemic β-blocker:
No additional effect on pulse or BP
↓ IOP lowering with ↑ oral dose
Use of systemic β-blocker can mask prior IOP elevation and cause pseudo-NTG picture

28. Beta-Blockers Carteolol 1% Intrinsic sympathomimetic activity
Theoretically causes less bronchoconstriction, bradycardia, vasoconstriction
Less ocular irritation
Better tolerated in dry eye patients

29. Beta-Blockers Betagan ® Levobunolol 0.25%, 0.5%
Slightly longer half-life than timolol; ? qd dosage
Betoptic-S® (betaxolol 0.25% ): β1-selective
Less pulmonary and CNS side effects
Less systemic absorption than timolol

30. Beta Blockers: Side Effects
Bronchospasm
Bradycardia, arrhythmia
CHF
Syncope
Hypotension
Depression
Sexual dysfunction

31. Beta-Blockers: Contraindications
Asthma (Reactive Airway Disease)
Bradycardia
Heart block
Acute CHF

32. Alpha 2 Agonists:Dosing & Preparations
Iopidine® (apraclonidine 0.5%, 1%)
BID-TID
- α1, α2
Decreases aqueous production
May lose efficacy after 4-6 months
Alphagan-P® (brimonidine 0.1%, 0.15%), generic brimonidine 0.2%
- α2-selective
↓aqueous production; ↑uveoscleral outflow
May lose efficacy after 1 year
Neuroprotection?

33. BRIMONIDINE : THE NEUROPROTECTIVE a2 AGONIST
Brimonidine neuroprotection may be mediated through up-regulation of Brain-derived neurotrophic factor BDNF in the retinal ganglion cells RGCs.
Brimonidine may be (potentially) used clinically as a neuroprotective agent.
Arch Ophthalmol. 2002;120:

34. Alpha 2 Agonists: IOP Response
Expected IOP lowering:
20-25%
Peak Effect
2 hours
Wash Out
1-3 weeks

35. Alpha 2 Agonists: IOP Response
A recent study conclude that Brimonidine 0.2% has a higher potency of lowering IOP than brimonidine Purite 0.15% at trough when used twice-daily. However, ocular allergic reaction was more frequent and severe with brimonidine 0.2% than with brimonidine Purite 0.15%.
Journal of Ocular Pharmacology and Therapeutics. 2007, 23(5):

36. Alpha 2 Agonists: IOP Response
One study suggests:
brimonidine purite BID= dorzolamide BID
???
British Journal of Ophthalmology 2004;88:

37. Alpha 2 Agonists: Side Effects
Follicular conjunctivitis
50% apraclonidine
15% (at least) brimonidine
Less with Alphagan P
Need more non-pharmaceutical company data
Fatigue, drowsiness
Eye lid retraction
Dry mouth
Hypotension

38. Alpha 2 Agonists: Side Effects
Apnea in infants and young children
weight > 20 Kg
age > 6 Years
Alternative glaucoma therapy should be considered.
Ophthalmology Volume 112, Issue 12, December 2005

39. CAIs : Dosing & Preparations
Topical
Trusopt® Dorzolamide 2%: BID – TID
Azopt® Brinzolamide 1%: BID – TID
Oral
Diamox® Acetazolamide: 250mg QID, SR 500 BID
Neptazane® Methazolamide: mg Once/Day-TID

40. CAIs: Mechanism of Action
Inhibit CA enzyme in ciliary body epithelium
Decrease aqueous production
Improve ocular blood flow?

41. Topical CAIs : IOP Response
Expected IOP lowering:
15-20%
Wash Out
Topical: 1 week
Oral: 3 days

42. Topical CAIs : Side Effects
Ocular surface irritation
Contact allergy
Contraindication:
Sulfonamide allergy

43. Oral CAIs: Side Effects
Paresthesias
Tinnitus
Depression
Loss of appetite
GI symptoms
Kidney stones
Metabolic acidosis
Electrolyte imbalance

44. Oral CAIs: Side Effects
Anaphylaxis
Stevens-Johnson Syndrome
Bone marrow dysfunction
Idiosyncratic
Can be any cell line
aplastic anemia most described
Some reversible some not
Potentially lethal

45. CAIs Oral is additive to topical (1-2mmHg)
Topical not additive to oral
Methazolamide 75% liver metabolized
Safer in renal disease
Eg. Diabetic with CRF and NVG

46. Parasympathomimetics: Dosing & Preparations
Pilocarpine 0.5% - 4% BID-QID
4% gel once daily (QHS)
Carbachol 0.75% - 3% BID-TID

47. Parasympathomimetics: Mechanism of Action
Increase TM outflow
Believed secondary to contraction of smooth muscle fibers inserting into scleral spur

48. Parasympathomimetics: IOP Response
Expected IOP lowering:
10-20 %
Lowers IOP by 1 hour post instillation
Wash Out:
3 days

49. Parasympathomimetics: Side Effects
Pro-inflammatory
Break down blood ocular barrier
Miosis
Brow ache (<~40 y.o.)
P.S.
Shallowing of A.C.
Possible worsening of pupil block RD
Cataract

50. Fixed Combination
Cosopt
Combigan
Xalacom
DuoTrav
Ganfort

51. Fixed Combination XALACOM QD = TIMOLOL BID + XALATAN QHS (1)
XALACOM QD > COSOPT BID (2)
XALACOM QD > BRIMONIDINE BID +
TIMOLO BID (3)
1-Ophthalmology Jan;113(1):70-6
2-Ophthalmology Feb;111(2):276-8.
3-Acta Ophthalmol Scand Jun;81(3):242-6

52. Fixed Combination
Martinez et all study showed a significantly higher IOP-lowering effect of a once-daily evening dose of the BTFC compared to that of a once- daily evening administration of the LTFC. (1)
(1) Current Medical Research and Opinion, Volume 23, Number 5, May 2007 , pp (8)

53. differences were not significant (p >0.207).
EXAMPLE
Main outcome measure
To evaluate the efficacies of bimatoprost and travoprost for lowering of IOP for the treatment of glaucoma and ocular HTN.
Result:
The mean reduction in the bimatoprost group were greater than the reduction in the travoprost group at every study visit, but these
differences were not significant (p >0.207).
Abstract conclusion: Bimatoprost provided greater mean IOP reduction than travoprost.
Br J Ophthalmology 2006; 90:

54. COMPLIANCE: THE HIDDEN CHALLENGE OF GLAUCOMA MANAGEMENT

55. Patient Compliance: Glaucoma
Patient compliance is a particularly important issue in glaucoma because:
Asymptomatic
Long term therapy
Benefit of treatment not apparent
Several medications
Expense of treatment
Inconvenience of treatment
Side effects of treatment
Ref: J of Glaucoma 1992; 1:

56. Patient Non-compliance: Glaucoma
Available literature suggests that between 28% and 58% of glaucoma patients do not use their medications as prescribed
Non compliance is probably 30%-40%
Ref: assessed on 27/03/04

57. Preservatives
BAK has demonstrated cytotoxic effects in cell culture, as well as in animal and human studies.
Physicians should consider treatment with new- generation preparations containing low-risk preservatives, especially in patients receiving multiple ophthalmic medications.
Adv Ther Sep-Oct;18(5):

58. Preservatives
A study on rats corneas suggest that glaucoma medications with low levels of BAK, alternative preservatives such as Purite®, or preservative-free formulations are more benign to the ocular surfaces.
Cornea Jul;23(5):490-6.

59. Preservatives
British Journal of Ophthalmology :

60. Preservatives Alphagan P Purite Alphagan 0,005% Lumigan 0,005%
Combigan %
Trusopt %
Cosopt %
Azopt %
Timoptic %
Betoptic %
Travatan %
Xalatan %
Xalacom %

61. A Little Perspective…
“The risk and cost, including side effects of treatment to lower pressure, must be weighed against the risk of pressure itself.”Hodapp

62. If you light a lamp for somebody , It will also brighten your path